Research
Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital
Published

High frequency of pathogenic germline variants within homologous recombination repair in patients with advanced cancer

Research output: Contribution to journalJournal articleResearchpeer-review

  1. Elevated polygenic burden for autism is associated with differential DNA methylation at birth

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Type 2 diabetes and obesity induce similar transcriptional reprogramming in human myocytes

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Relation between NOD2 genotype and changes in innate signaling in Crohn's disease on mRNA and miRNA levels

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Roux-en-Y gastric bypass surgery of morbidly obese patients induces swift and persistent changes of the individual gut microbiota

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. Testing NTRK testing: Wet-lab and in silico comparison of RNA-based targeted sequencing assays

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Behandling af tymom og thymuskarcinom

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Variant in ERAP1 promoter region is associated with low expression in a patient with a Behçet-like MHC-I-opathy

    Research output: Contribution to journalJournal articleResearchpeer-review

View graph of relations

Genomic screening of cancer patients for predisposing variants is traditionally based on age at onset, family history and type of cancer. Whereas the clinical guidelines have proven efficient in identifying families exhibiting classical attributes of hereditary cancer, the frequency of patients with alternative presentations is unclear. We identified and characterized germline variants in 636 patients with advanced solid cancer using whole exome sequencing. Pathogenic and likely pathogenic germline variants among 168 genes associated with hereditary cancer were considered. These variants were identified in 17.8% of the patients and within a wide range of cancer types. In particular, patients with mesothelioma, ovarian cancer, cervical cancer, urothelial cancer, and cancer of unknown primary origin displayed high frequencies of pathogenic variants. Variants were predominantly found in DNA-repair pathways and about half were within genes involved in homologous recombination repair. Twenty-two BRCA1 and BRCA2 germline variants were identified in 12 different cancer types, of which 10 (45%) were not previously identified in these patients based on the current clinical guidelines. Loss of heterozygosity and somatic second hits were identified in several of the affected genes, supporting possible causality for cancer development. A potential treatment target based on the pathogenic germline variant could be suggested in 25 patients (4%). The study demonstrates a high frequency of pathogenic germline variants in the homologous recombination pathway in patients with advanced solid cancers. We infer that genetic screening in this group of patients may reveal high-risk families and identify patients with potential PARP inhibitor sensitive tumors.

Original languageEnglish
JournalGenome Medicine
Volume4
Pages (from-to)13
ISSN1756-994X
DOIs
Publication statusPublished - 2019

ID: 58596959